The overall goal of this project is to fully describe and characterize the role of the Killer-cell Immunoglobulinlike Receptor (KIR) loci in neurological disease. This project is submitted as a key component of the larger INDIGO (Immunogenetics of Neurological DIseases working GrOup) consortium effort. This international collaboration builds on the driving principle that through collaboration and synergy, collectively we will make rapid progress towards understanding the genetic causes of neuroinflammation and neurodegeneration. Using modern sequencing methods and state of the art bioinformatics and analytics, the purpose of Project 2 is to establish and refine the association of KIR genetic polymorphism with multiple sclerosis, myasthenia gravis, neuromyelitis optica, Parkinson?s disease and schizophrenia. Central to immunity and critically important for human health, KIR molecules and their Human Leukocyte Antigen (HLA) ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. Building on the work by the principal and co-investigators and others, and fueled by the discovery of combinatorial associations of KIR and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, the field of immunogenomic research is now flourishing. However, studies to-date of KIR in diseases of the central nervous system have been few and limited to very low resolution genotyping. Synergized with Project 1, which focuses on variation of HLA in the same cohorts, this project will ascertain the impact of KIR variation, including promoter region polymorphism, and the interaction of KIR with HLA in neurological disease. In the proposed work we will characterize the nature and extent of the association of KIR variation achieved via high-throughput, high-resolution Next-Generation Sequencing (NGS) KIR genotyping and applied across a set of established and well-characterized cohorts of unprecedented size and diversity with respect to disease, phenotype and ethnicity. Characterization of KIR variation at high resolution will permit us to fully appreciate the impact of this diversity across a wide range of neurological diseases. We will leverage the extensive available experience within our consortium in clinical neuroscience, immunogenetics, and immunology, with sophisticated data management, bioinformatics, and statistical analysis expertise, coupled with state of the art laboratory methodology to improve our understanding of the role of KIR in neurological disease.